Traumatic brain injury (TBI) is a leading cause of death and disability that has no specific treatment. Programmed cell death (PCD) that occurs after TBI is a potential therapeutic target, however, mechanisms that initiate PCD after TBI are not well understood. Endogenous death receptors of the tumor necrosis super-family are transmembrane proteins that can initiate PCD. Activation of death receptors leads to formation of a death inducing signaling complex (DISC) that initiates PCD by activating caspase 8 and the pro-apoptotic bcl2 family member Bid. We have generated preliminary data demonstrating up-regulation of death receptors and formation of a DISC in injured brain after TBI in mice. We hypothesize that death receptors of the TNF super-family promote neuronal death and secondary injury after experimental TBI. To examine this hypothesis we propose the following Specific Aims: 1) Extend the development of a controlled cortical impact (CCI) model of TBI in mice and characterize the delayed cell death component, 2) determine whether mechanisms of cell death after CCI involve PCD, 3) determine the co-localization and time course of expression of death receptors, their specific ligands, and other upstream mediators for initiation of caspase activation and cell death in neurons and glia after TBI, and 4) determine if strategies that inhibit death receptors or their downstream targets reduce neuropathology (contusion volume, histology) and improve functional outcome (cognitive and motor) after CCI. If death receptors such as fas and TNF-alpha play a role in PCD after TBI, then these studies may lead to specific treatments for secondary injury after TBI. This proposal will provide an opportunity for experience that is essential for my long-term goal to pursue a career in clinically related brain and cell death research. The Neuroscience Center at the Massachusetts General Hospital and the faculty at Harvard Medical School provide an outstanding training environment to study key mechanisms of TBI and cell death. This experience will be reinforced by participation in the Boston Cell Death Club and coursework offered at the Harvard Medical School.